Felbamate, also known as 2-phenyl-1,3-propanediol dicarbamate, having the structure of Formula (I),
Felbamate is a well known antiepileptic drug described in U.S. Pat. Nos. 4,978,680 and 5,082,861.
Several processes for the synthesis of Felbamate have been described, including the methods disclosed in U.S. Pat. Nos. 2,884,444, 4,868,327, 4,982,016, 5,091,595 and 5,500,484, as well as WO 94/06737 and WO 94/27491, all of which are incorporated by reference.
The compound 2-phenyl-1,3-propanediol of Formula (II)
is used as an intermediate for Felbamate synthesis. U.S. Pat. Nos. 2,884,444, 4,982,016 and 5,091,595 teach the synthesis of 2-phenyl-1,3-propanediol by reduction of the corresponding 2-substituted malonic ester, diethyl phenylmalonate, with metal hydride complexes. However, the above methods require costly and extremely flammable agents for reducing diethyl phenylmalonate to 2-phenyl-1,3-propanediol such as borane dimethyl sulfide, lithium aluminum hydride and diisobutyl aluminum hydride. The high cost and hazardous nature of these reducing agents render such processes unsatisfactory for commercial use. In addition, the yield of the 2-phenyl-1,3-propanediol preparation using the above methods is between about 30% to about 50% and the impurity levels were found to be relatively high.
Zhao et al. and Goto M. et al. (Chinese Journal of New Drugs, 2005, Vol 14, No. 12 and Research Reports of Toyama National College of Technology, 2001, Vol 35, respectively) disclose 2-phenyl-1,3-propanediol preparation by the reduction of Diethyl Phenylmalonate with the nonflammable reducing agent Sodium Borohydride in the presence of Hydrochloric acid. However, the above method suffers from the drawback of high impurity levels and low yields of the product.
In view of the above it would be desirable to provide faster, facile, safer and more efficient process for the preparation of 2-phenyl-1,3-propanediol.